Variation in the risk for substance use disorders(SUD) results from the interaction of genetic and environmental factors. Molecular genetic studies may help disentangle these factors. Few human genetic polymorphisms, however, have been studied in relation to the liability to SUD. Among these loci, the genes encoding dopamine receptors and monoamine oxidase (A and B forms) attract special attention because of their demonstrated or hypothesized involved in the risk for SUD. Furthermore, our pilot data support an association between polymorphisms at the dopamine D5 receptor and MAOA genes and the risk for SUD. We have the following specific aims. Aim 1. Evaluate association of polymorphisms at the dopamine receptor genes as well as genes encoding enzymes involved in the associated polymorphisms at the dopamine receptor genes as well as genes encoding enzymes involved in the metabolism of neurotransmitters (e.g., monoamine oxidases A and B), separately and as haplotypes for multiple markers, with the liability to SUD; Aim 2. Determine the influence of the same DNA polymorphisms on temperament and personality characteristics. Evaluate the influence of personality characteristics. Evaluate the influence of personality characteristics on the association between the liability to substance dependence and the DNA polymorphisms; Aim 3. Evaluate the effects of environmental factors shown to influence the risk of SUD on the variation in liability to SUD and its relationship with genetic polymorphisms; and Aim 4. Determine the transmissibility of the liability to SUD; specifically determine the contribution of particular genetic and environmental factors into the transmissible and neotransmissible components of liability variation. The proposed research will examine the role of DNA polymorphisms, personality and environmental factors in variations in the liability to SUD. Even though the effects of single genes may be small, their attributable risk may be large because of a high frequency of high-risk associated alleles in the population. The combined effect may be substantial. Moreover, the effect of measures of drug abuse prevention that could be developed based on the knowledge of genetic mechanisms contributing into the SUD risk variation in the population may be greater than the "natural" contribution of such mechanisms. The results will allow for more accurate estimation of the risk for SUD and suggest approaches for prevention.